Epithelial ovarian cancer is the most common gynecological malignancy and the sixth most common cancer in women worldwide, with highly aggressive natural history causing almost 125,000 deaths yearly. Despite advances in detection and cytotoxic therapies, only 30% of patients with advanced-stage ovarian cancer survive 5 years after initial diagnosis. The high mortality of this disease is mainly due to late stage diagnosis for more than 70% of ovarian cancers. In fact, when ovarian cancer is diagnosed in its early stage, that is still organ-confined, the five-year survival rate exceeds 90%. Unfortunately, only 19% of all ovarian cancers are diagnosed at this early stage. Indeed, this rather poor prognosis is due to (i) the insidious asymptomatic nature of this disease in its early onset, (ii) the lack of robust and minimally invasive methods for early detection, and (iii) tumor resistance to chemotherapy. The vast majority of human ovarian carcinomas are represented by ovarian epithelial cancers (OECs), deriving from the ovarian surface epithelium (OSE).
Ovarian adenocarcinomas occur as four major histological subtypes, serous, mucinous, endometrioid and clear cell, with serous being the most common. Current data indicate that each of these histological types is associated with distinct morphologic and molecular genetic alterations, but further investigations of the molecular mechanisms promoting ovarian cancer are necessary to determine how each of the subtypes emerges.
Over the last five years expression profiling technologies greatly improved, thus expanding the knowledge on cancer etiology and biomarkers with clinical applications. However, although these technologies have provided most of the new biomarkers with potential use for diagnosis, drug development, and tailored therapy, they have so far shed little insight into the detailed mechanisms at the origin of this neoplasia, thus suggesting that ovarian tumorigenesis may occur through novel or poorly characterized pathways.
A new class of small non-coding RNAs, named microRNAs, was recently discovered and shown to regulate gene expression at post-transcriptional level, for the most part by binding through partial sequence homology to the 3′ untranslated region (3′ UTR) of target mRNAs, and causing block of translation and/or mRNA degradation. MicroRNAs are 19-25 nt long molecules cleaved from 70-100 nt hairpin pre-miRNA precursors. The precursor is cleaved by cytoplasmic RNase III Dicer into ˜22-nt miRNA duplex: one strand (miRNA*) of the short-lived duplex is degraded, while the other strand, that serves as mature miRNA, is incorporated into the RNA-induced silencing complex (RISC) and drives the selection of target mRNAs containing antisense sequences.
Several studies have demonstrated that miRNAs play important roles in essential processes, such as differentiation, cell growth and cell death.
Moreover, it has been shown that miRNAs are aberrantly expressed or mutated in cancers, suggesting that they may play a role as a novel class of oncogenes or tumor suppressor genes, depending on the targets they regulate: let-7, downregulated in lung cancer, suppresses RAS and HMGA2 mir-15 and mir-16, deleted or down-regulated in leukemia, suppress BCL2; mir-17-5p and mir-20a control the balance of cell death and proliferation driven by the proto-oncogene c-Myc.
Clear evidences indicate that miRNA polycistron mir-17-92 acts as an oncogene in lymphoma and lung cancer; mir-372 and mir-373 are novel oncogenes in testicular germ cell tumors by numbing p53 pathway, miR-155, overexpressed in B cell lymphomas and solid tumors, leads to the development of B cell malignancies in an in vivo model of transgenic mice.
The use of microRNA microarray technologies has been used as a powerful tool to recognize microRNAs differentially expressed between normal and tumor samples, and also to identify miRNA expression signatures associated with well-defined clinico-pathological features and disease outcome. Several studies have also investigated the molecular mechanisms leading to an aberrant microRNAs expression, identifying the presence of genomic abnormalities in microRNA genes. More recently, few evidences have shown that microRNAs genes may be regulated also by epigenetic mechanisms, as changes in genomic DNA methylation pattern: miR-127 and miR-124a are transcriptionally inactivated by CpG island hypermethylation, while in lung cancer the overexpression of let-7a-3 seems to be due to DNA hypomethylation.
In spite of considerable research into therapies for ovarian cancer, ovarian cancer remains difficult to diagnose and treat effectively, and the mortality observed in patients indicates that improvements are needed in the diagnosis, treatment and prevention of the disease.